2-(substituted-methyl)-5,6-dihydro-1,4-oxathiin-3-carboxamides

ABSTRACT

Chemicals of the formula   WHEREIN X can be various substituents, particularly halogen and univalent radicals containing a hetero atom, and Y is carboxamide, are useful as agricultural fungicides. The carboxamide may be variously substituted. Examples are 2chloromethyl-5,6-dihydro-1,4-oxathiin-3-carboxanilide (X chlorine, Y phenylcarbamoyl, n zero) and 5,6-dihydro-2thiocyanomethyl-1,4-oxathiin-3-carboxanilide (X thiocyano, Y phenylcarbamoyl, n zero).

United States Patent [1 1 Knight et al. 1 Apr. 17, 1973 2-(SUBSTITUTED-METHYL)-5,6-

DIHYDRO-l ,4-OXATHIlN-3- Primary Examiner-Alex Mazel CARBQXAMIDES Assistant Examiner-Jose Tovar Art r -James J. Lon [75] Inventors: Barry 1. Knight; Michael Curcumel- 0 My g li-Rodostamo; Marshall Kll lka, all Of 57 ABSTRACT Guelph, Ontario, Canada; Bogislav Von Sc'hmeling, Hamden, Conn. Chemlcals of the formula 1 [73] Assignee: Uniroyal, Inc. 0

HzG E-CH2X '[22] Filed: Sept. 8 1970 C C Y r Hz [21] Appl. No.: 78,344 8 [52] US'C] 260/3271, 260/247 1 260/306 wherein X can be various substituents, particularly I 424/276; halogen and univalent radicals containing a hetero [51] 1 Int Cl C07d 89/14 atom, and Y is carboxamide, are useful as agricultural [J58] Fie'ld 260/327 P fungicides. The carboxamide may be variously substituted. Examples are 2-ch1or0:methyl5,6-dihydro- 1,4-oxathiin-3-carb0xanilide (X =-ch1orine, Y phen- [56] References cued ylcarbamoyl, n 1 zero) and 5,6-dihydro-2-thio- UNlTED STATES PATENTS cyanornethyl-1,4-oxathiin-3-carboxanilide (X thiocyano, Y phenylcarbamoyl, n zero). 3,082,214 3/1963 Bluestone ..260/327 P 2,158,019 5/1939 Clifford ..260/327 P 5 Claims, N0 Drawings 2-(SUBSTITUTED-METHYL)-5 ,6-DII-IYDRO- l ,4- OXATHIIN-3-CARBOXAMIDES BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to new chemicals and to the control of agricultural fungus disease in plants by application of such chemicals.

2. Description of the Prior Art 5 ,6-Dihydro-2-methyll ,4-oxathiin-3-carboxamides are known as agricultural fungicides, as disclosed in U.S. Pat. No. 3,249,499 issued to von Schmeling et al. May 3, 1966, No. 3,393,202 issued to Kulka et al. July 16, 1968, No. 3,399,214 issued to Kulka et al. Aug. 27,

mides) where the 6-alkyl substituent has from one to five carbonatoms, to corresponding N-sulfenyl chemicals, for use as fungicides. The present chemicals differ from the starting chemicals of the French patent in that the present chemicals have a substituted-methyl group in the 2-position, .whereas the starting chemicals of the French patent have in the corresponding position (there called the 6-position) an unsubstituted C, C alkyl group.

SUMMARY THE INVENTION The invention is concerned with new chemicals com prising 5,6-dihydro-l ,4-oxathiin-3-carboxamides with a mono-substituted methyl group at position 2 as well as to thecontrol of plant fungal diseases by application of 'such chemicals.

DETAILED DISCLOSURE The chemicals of the invention are Z-(substitutedmethyl)-5,6-dihydro- 1 ,4-oxathiin-3-carboxamides having from zero to two oxygen atoms attached to the sulfur at the. 4-position, wherein the 2-(substitutedmethyl) group may be represented by the formula CH X, X being a monovalent substituent other than hydrogen or alkyl, notably halogen (e.g., chlorine,

bromine, etc.), or other substituent containing a hetero atom (that is, an atom other than hydrogen or carbon). Many such chemicals are represented by formula I:

0 H26 CH2X H, I -C-N-Ri n R1 I wherein n is 0, 1 or 2. R, and R, are the same or different and may have various values as disclosed for example in the U. S. patents referred to above, particularly hydrogen. Nth, and univalent organic groups. Of the latter the following may be mentioned: alkyl. aryl,

aralkyl, alkaryl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclic radicals, and various combinations thereof; also monoand poly-substituted derivatives of the above groups (e.g., p-methoxyphenyl). X is ordinarily halogen (e.g., chlorine, bromine, etc.) ,alkoxy, acyloxy, alkylamino, arylamino, aralkylamino, alkarylamino, alkylthio, arylthio, aralkylthio, alkarylthio, mercapto, morpholino, and various groups derived from the above by substitution, such as alkoxythionothio, thiocyano, halophenylthio, monoand dialkylthiocarbamoylthio.

The chemicals of the invention may be used for various purposes. Thus they may be employed as microbiocides, such as fungicides, and as intermediates for the synthesis of other chemicals.

The compounds with n O, X halogen, may be prepared by halogenation of the corresponding dihydrooxathiins in which X H (U.S. Pat. No. 3,393,202 cited above). Thus 2-chloromethyl-5,6- dihydro 1,4-oxathiin-3-carboxanilide (I, n O, R, H, R C I-I X Cl) may be prepared by chlorination of 5 ,6-dihydro-2-methyl- 1 ,4-oxathiin-3-carboxanilide (I, n O, R,= X H, R',= C I-I with sulfuryl chloride.

The halogenomethyl sulfides (I, n= 0, X halogen) may be used for the synthesis of the other sulfides of the invention (I, n O) by conventional substitution reactions (Examples 2 9).

The sulfoxides and sulfones (I, n l and 2) may be prepared by oxidation of the corresponding sulfides (I, n= 0) with hydrogen peroxide at the appropriate temperature (U.S. Pat. No. 3,399,214 cited above). Thus 2-chloromethyl-5,6-dihydro-1,4-oxathiin-3-carboxanilide-4,4-dioxide (I, n 2, R, H, R, C H X Cl) maybe obtained by hydrogen peroxide oxidation of the corresponding chloromethyl sulfide (I, n O, R, H, R,=C H ,X=Cl)at i The halogenomethyl sulfoxides and sulfones (I, n l and 2, X halogen) may be used as intermediates in the synthesis, by standard substitution reactions, of other sulfoxides and sulfones of the present invention. 7

The following examples will serveto illustrate the practice of the invention in more detail. 7

EXAMPLE I 2-Chloromethyl-5,6-dihydro-1,4oxathiin-3- carboxanilide (I, n O, R, H, R, C l-I X Cl) with water and a little benzene. Yield 72.0 g (84 per-' cent);mp 103-l05. Method 2 To a stirred suspension of.5,6-dihydro-2-methyl-1,4- oxathiin-3-carboxanilide (25.0 g, 0.106 mole) in toluene ml) wasadded dropwise'sulfuryl chloride (14.0 g, 0.104 mole) at such a rate as to keep the tem perature be low 30. Stirring was continued for 3 hours after the addition was completed. Air was then blown lightly over the reaction mixture to remove HCl and S and to reduce the solution volume to about 100 ml. The reaction mixture was cooled overnight to induce crystallization. The solid product was filtered off and washed with a little toluene. Yield 21.0 g (73 percent); mp l02l04.

EXAMPLE 2 2-Ethoxymethyl-5 ,6-dihydro-l ,4-oxathiin-3- carboxanilide (l, n 0, R H, R C H X OC H A solution of 2-chloromethyl-5,6-dihydro-1,4-oxathiin-3-carboxanilide (15.0 g, 0.055 mole) and K CO (4.0 g, 0.029 mole) in 95 percent ethanol (200 ml) and water ml) was refluxed for 2 hours. The reaction mixture was taken to dryness under reduced pressure and the residue dissolved in chloroform. The resulting solution was washed with water and the chloroform removed under reduced pressure. The product was recrystallized from 95 percent ethanol. Yield 9.3 g (60 percent); mp 8182.

EXAMPLE 3 2-Acetoxymethyl-5 ,6-dihydro-1,4-oxathiin-3- carboxanilide (l, n O, R H, R; C H X OCOCH A solution of 2-chloromethyl-5,6-dihydro-l ,4-oxathiin-3-carboxanilide (40.0 g, 0.148 mole) and potassium acetate (15.0 g, 0.153 mole) in glacial acetic acid (400 ml) was stirred at 7080 for 3 hours. The reaction mixture was diluted with water (1.5 l) and extracted with chloroform. The chloroform was removed under reduced pressure and the residue recrystallized from 95 percent ethanol. Yield 35.0 g (80 percent); mp 9294.

EXAMPLE 4 2-Diethylaminomethyl-5,6-dihydro-l ,4-oxathiin-3- carboxanilide (l, n 0, R H, R C H X N 2 5)2) A solution of 2-chloromethyl-5,6-dihydro-l,4-oxathiin-3-carboxanilide (5.0 g, 0.019 mole) in diethylamine (50 ml) was refluxed for 1 .hour. The diethylamine hydrochloride formed was removed by filtration and the filtrate taken to dryness under reduced pressure. The crude product was recrystallized from 95 percent ethanol. Yield 4.5 g (79 percent); mp

EXAMPLE 5 2-[ [5 ,6-Dihydro-3-(phenylcarbamoyl)- l ,4-oxathiin-2- yl]methyl]-2-thiopseudourea monohydrochloride (l, n 0, R 0, R H, R C H X SC(Nl-l )NH'HCl) A solution of 2-chloromethyl-5,6-dihydro,-1,4-oxathiin-3-carboxanilide (27.0 g, 0.100 mole) and thiourea (9.0 g, 0.118 mole) in 95 percent ethanol (150 ml) was refluxed for 30 min., during which time the thiouronium salt began to precipitate. The reaction mixture was cooled, and the product filtered off and washed with ethanol. Yield 31.0 g (90 percent); mp 224226" (dec.).

EXAMPLE 6 5 ,6-Dihydro-2-mercaptomethyl-1,4-oxathiin-3- carboxanilide (l, n =0, R H, R C H X SH) 2-[ [5 ,6-Dihydro-3-(phenylcarbamoyl)-l ,4-oxathiin- 2-yl]methyl]-2-thiopseudourea monohydrochloride (5.0 g, 0.014 mole) was dissolved in aqueous 2N NaOH and the resulting solution stirred for 20 min. The reaction mixture was filtered and the filtrate acidified with dilute aqueous HCl. The precipitate formed was collected and recrystallized from 95 percent ethanol. Yield 3,5 g percent); mp l10-l 1 1.

EXAMPLE 7 2-( 2-Benzothiazolylthiomethyl)-5 ,6-dihydro-1,4- oxathiin-3-carboxanilide (l, n O, R R C H A solution of 2-chloromethyl-5,6-dihydro-1,4-oxathiin-3carboxanilide (13.5 g, 0.050 mole) and 2-mercaptobenzothiazole (8.5 g, 0.050 mole) in percent ethanol ml) was refluxed for 1 hours. The reaction mixture was cooled to 10 and the solid product collected and washed with ethanol. Yield 10.4 g (52 percent); mp l65-168.

EXAMPLE 8 2-(0,0-Diethylthiophosphonothiomethyl)-5,6- dihydrol ,4-oxathiin-3-carboxanilide (l, n 0, R H, 2 a 5. 2 s)2) EXAMPLE 9 5 ,6-Dihydro-2-thiocyanomethyll ,4-oxathiin-3 carboxanilide (l, n 0, R H, R, C l-l X SCN) To a stirred solution of 2-chloromethyl-5,6-dihydrol,4-oxathiin-3-carboxanilide (2.7 5, 0.010 mole) in acetonitrile (30 ml) was added dropwise a solution of KSCN (1.2 g, 0.012 mole) in water (3 ml). After the addition was completed, the reaction mixture was heated on a steam-bath for 5 min., cooled and poured into cold water (800 ml). The crystalline solid formed was filtered off. Yield 2.6 g (89 percent); recrystallization from methanol yielded material melting at ll3l 15.

EXAMPLE 2-Chloromethyl-5 ,6-dihydro-l ,4-oxathiin- 3carboxanilide-4-oxide (I, n 1, R H, R C6H5, X Cl) To a stirred solutionof 2-chloromethyl-5,6-dihydrol,4-oxathiin-3-carboxanilide (27.0g, 0.100 mole) in glacial acetic acid (50 ml) and water (5 ml) was added dropwise a solution of percent hydrogen peroxide (12 ml, 0.106 mole) in acetic acid (13 ml). The reaction temperature was keptbelow 15 by use of an icebath during the addition and for a further 5 hours. The reaction mixture was then diluted with water (300 ml) and neutralizedby the careful addition of sodium bicarbonate. The precipitate formed was collected and recrystallized from ethanol. Yield 13.0 g percent);

mp l49-150.

' EXAMPLE 11 2-Chloromethy1-5 ,6-dihydro-l ,4-oxathiin-3- carboxanilide-4,4-dioxide (l, n 2, R l-LR, C H X Cl) To a solutionof 2-chloromethyl-5.6-dihydro-1,4-oxathiin-3-carboxanilide (15.0 g, 0.056 mole) in glacial acetic acid ml) was added a solution of 30 percent hydrogen peroxide (13.2 ml, 0.116 mole). The resulting solution was heated at for 2.5 hours. The dark solution was taken to dryness in vacuo and the residue dissolved in benzene. The benzene solution was cooled to induce crystallization and the product collected and washed with methanol. Yield 11.0 g (65 percent); mp 136-l38 (dec.)

EXAMPLE 12 2-p-Chlorophenylthiomethyl-5 ,6-dihydro-1,4-oxathiin- 3-carboxanilide-4-oxide (l, n 1, R,= H,R C 11 Method 1 To a stirred solution of 2-p-chloropheny1thiomethyl- 5,6-dihydro-1,4-oxathiin-3-carboxanilide (16.4 g,

0.044 mole) in glacial acetic acid (40 ml) and water (5 ml) was added dropwise 30 percent hydrogen peroxide (5.3 ml, 0.047 mole) in acetic acid (5 ml). The reaction temperature was kept below 15 by cooling in an ice bath. After standing overnight in a refrigerator, the

in benzene. The benzene solution was washed with dilute aqueous NaOH and water. The benzene was removed in vacuo and the residue was crystallized from percent ethanol. Yield 0.5 g (20 percent); mp 144-146.

The foregoing and further examples are summarized in the following Table l. the structural characteristics n, R R and X refer to general structure 1. i

TABLE 1 M.P., Yiultl. R R1 t1(1gl't1(1S.]l0l'C(-ll1- H C(1H5 Cl 103-105 341 H 01H 1 1) C11 1 111-82 1111 II (31115 0 C 0 CH3 112-04 1111 H C 115 N(C:H5)z -112 TJ H C SC(NH;)NH, 1101 224-226 00 II CsHs SH 110-111 00 7 0 H Calls -168 52 1-1 11 11 (1111.1 HI(S)(()C3H5): 1114-1011 74 11, 11 11 (1 11;. MIN 113-115 1111 111.. 1 11 11111:. 111 1411-1511 45 11 u 11 1 111. 111 1311-1311 115 11 H p I 1 1 11; 11 11 11111:. s11(s)1111,1|;. 11111-11111 7:1 17 11 1| 1 1,, S(1(S)Nll(!1 |l 1:104:12 115 Ill (1 ll (111: N(("zll.r)g 75-78 (13 From theforegoing it will be manifest that typical 2- (substituted-methyl )-5 ,6-dihydrol ,4-oxathiin-3-carboxamides of the invention may be represented by the formula TABLE I continued a M.P., Yield. Example 11 R1 R1 X degrees percent 0 H CH5 SC(NH)NH,HC1 219-221 74 22... 0 11 W SC(S)0C;H5 106-108 78 -Clia 23 0 11 OCOCH; 113-120 31 7"CII3 0 CH; C1H5 (11 131-133 64 0 OH; 01115 SON 136-138 32 S CN(CH3):1

Y s s- -01 (|1-CH2CCH:1

CH7 CH:

(Ill; 1111,

33m 0 0 11 (1,11,, 111 5M3 711 34. 2. n 0,117. 0,115 -sc,11. 011 no 35.". 5. U 0111:; 01",; 003115 ()il "1 311. 0 0,11 (1,11 --N((J;ll 011 112 38 1. 0 CH. 011. f 011 83 I 5 Z 5 N 311.; 11 0,115 0,115 --oooo1n on 71 40 2 c 11 c 11 01 011 111i EXAMPLE 30 0 v 50 IhC F-CHQX' 2-p-Chl0rophenylthiomethyl-5,6-dihydro-l ,4-oxathiinm 3-N-cyclohexylcarboxam1de (l, n O, R, H, R

cyclohexyl, X -SC H Cl-p) wherein:

n is O, l or 2; X is a monovalent substituent other than hydrogen or alkyl, notably halogen (e.g., chlorine, bromine; etc.),

, preferred monovalent 9 SP(S)(OC,H -SC(S)C H --SC(S)NHC H and SC(S)N(CH and Y is carbamoyl (whether substituted or unsubstituted).

In the carbamoyl group as represented by (its R and R are of course both hydrogen in the unsubstituted-moiety, whereas in the substituted moiety one or both Rs are other than hydrogen, as in such groups as lower alkyl, phenyl, lower alkylphenyl, lower alkoxy phenyl, and cyclohex- An interesting class of chemicals of the invention are those in which the substitution on the 2-methyl group is through a sulfur atom, as represented by the formula:

hydrogen, cyano, or a monovalent organic group such as lower alkyl, phenyl, chlorophenyl, C(NH )NH.

The. chemicals of the invention are useful for the control, in vivo or in'vitro, ofsuch microorganisms as fungi, especially in agricultural uses, including thecontrol of vegetable andfruit diseases such as blights and leafs'p'ots.

in agricultural applications, the chemical may be applied directly to plants (e.g., seeds, foliage) or to soil in which plant life is growing or is to be grown, to protect the plant life against the harmful effects of such pathogenic microbes as fungi. For example, the chemical may be applied to seeds by tumbling the chemical with the seeds, either alone or in admixture with a powdered solid carrier, to coat the seeds Typical powdered solid carriers are the various mineral silicates, e.g., mica, talc, pyrophillite, and clays. The chemical may also be'applied to the seeds in admixture with a conventional surface-active wetting agent, with or without additional powdered solid carrier, as by first wetting the mixture with a small amount of water and then tumbling the seeds in the slurry. The surface-active wetting agents that may be used with the chemical may be any of the conventional anionic, non-ionic, or cationic surface-active agents. Such surface-active agents are well known and detailed examples of the same are given in r U. S. Pat. No. 2,547,724, columns 3 and 4. As a seed protectant, the amount of the chemical coated on the seeds will be 5 4 to 12 ounces per hundred pounds of the seed. As a soil treatment for fungi and the like, the chemical may be applied as a dust in admixture with sand or soil or a powdered solid carrier such as a mineral silicate, with or without an additional surfaceactive wetting agent, to the furrows with the planting of the seeds, or the chemical may be applied as an aqueous spray, if desired including a surfaceactive dispersing agent, or a surface-active dispersing agent and a powdered solid carrier, to the seed rows before, or with, or after planting the seeds. As a soil treatment, the amount of the chemical applied to the seed rows the equivalentof an area 2 inches .wide and 2 inches deep to parallel rows in one direction a distance of 40 inches apart. Also, as a soil treatment, the chemical may be applied broadcast as a similar dust or aqueous spray with an application rate of l .0 to pounds per acre. As a foliage treatment (e.g., fungicide), the chemical may be applied to growing plants at a rate of A to 10 pounds per acre. Such application is generally as an aqueous spray which also contains a surface-active dispersing agent, with or without a powdered solid carrier or a hydrocarbon solvent. Thesesprays usually are repeated at time intervals ranging from, 3 days to 2 weeks during the growing seasomTypical formulations are as follows:

Chemicals of the invention distinguish themselves from prior oxathiins by exhibiting unexpectedly greater activity against certain fungi, i.e., Altemqriafsolizni, a Deuteromycete which is the causal organismof To-- mato Early Blight, and interesting'activity against other fungi, i.e., Uromyces phaseoli, a Basidiomycete, the causal organism of Bean Rust.

The following examples illustrate the biocidal activity of the chemicals.

EXAMPLE41 This example evaluates chemicals of the invention as I foliage fungicides by their ability to protect plants from subsequent infection by fungus diseases. procedure employed is exactly as described in Example 7 of U. S. Pat. No. 3,402,241, involving Tomato Early Blight caused by Alternaria solani. The results with various chemicals of the invention are shown in Table II,

while the data in Table ll confirms th effectiveness of the Example lchemical at various concentrations.

TABLE II Tomato Early Blight Test Percent Disease Control at PPM Chemical 500 2000 The EX. 1 93 99 Ex. I l 84 85 Ex. 18 75 90 Ex. 21 35 90 Ex. 25 85 95 Ex. 2 25 50 EX. l3 25 80 Ex. 4 77 91 Ex. 27 77 88 TABLE III Tomato Early Blight Test With Chemical of Ex. 1

PPM Percent Control I25 83 250 91 500 94 2000 99 EXAMPLE 42 The ability to control plant diseases which are already established in the plants (systemic activity) is evaluated by employing. the technique described in US. Pat. No. 3,402,241, Example I. The organism is the Bean Rust Uromyces phaseoli typica Arth., in snapbean plants. The results are shown in Table IV.

TABLE IV Systemic Fungicidal Activity Against Bean Rust Uromycer phaseoll Percent Control at PPM Chemical 500 2000 Ex. 1 65 I Ex. 21 t 25 90 EXAMPLE 43 Example 41 is repeated-using the chemicals shown in TAble V, with the results shown.

TABLE V Tomato Early Blight Test Percent Disease Control at PPM H Chemical 7 500 2000 Ex. 6 25 Ex. 9 77 89 Ex. 12 4O 80 Ex. 7 50 75 Ex. 16 68 82 Ex. 28 57 62 Ex. 8 50 80 Ex. 17 50 50 wherein R is hydrogen, methyl or ethyl,.R is phenyl. v

methylphenyl, methoxyphenyl, cyclohexyl, or tertiary octyl and X is chloro.

2. A chemical as in claim 1 in which R, is hydrogen and R is phenyl.

3. A chemical as in claim 1 which is 2-chloromethyl- 5,6-dihydro-1,4-oxathiin-3-carboxanilide.

4. A chemical as in claim 1 which is 2-chloromethyl- 5,6-dihydrol ,4-oxathiin-3-(N-methyl) carboxanilide.

5. A chemical as in claim 1 which is 2-chloromethyl- 5 ,o-dihydrol ,4-oxathiin-3-(m-methyl) carboxanilide.

5,6-dihydro-2- 

2. A chemical as in claim 1 in which R1 is hydrogen and R2 is phenyl.
 3. A chemical as in claim 1 which is 2-chloromethyl-5,6-dihydro-1,4-oxathiin-3-carboxanilide.
 4. A chemical as in claim 1 which is 2-chloromethyl-5,6-dihydro-1,4-oxathiin-3-(N-methyl) carboxanilide.
 5. A chemical as in claim 1 which is 2-chloromethyl-5,6-dihydro-1,4-oxathiin-3-(m-methyl) carboxanilide. 